Selective Vulnerability. A striking feature of neurodegenerative disorders is the exquisite specificity of the disease processes for particular types of neurons. For example, in PD there is extensive destruction of the dopaminergic neurons of the substantia nigra, whereas neurons in the cortex and many other areas of the brain are unaffected. In contrast, neural injury in AD is most severe in the hippocampus and neocortex, and even within the cortex, the loss of neurons is not uniform but varies dramatically in different functional regions (Arnold et al., 1991). Even more striking is the observation that in HD the mutant gene responsible for the disorder is expressed throughout the brain and in many other organs, yet the pathological changes are most prominent in the neostriatum (Landwehrmeyer et al., 1995). In ALS, there is loss of spinal motor neurons and the cortical neurons that provide their descending input (Tandan and Bradley, 1985). The diversity of these patterns of neural degeneration suggests that the process of neural injury results from the interaction of genetic and environmental influences with the intrinsic physiological characteristics of the affected populations of neurons. The intrinsic factors may include susceptibility to excitotoxic injury, regional variation in capacity for oxidative metabolism, and the production of toxic free radicals as by-products of cellular metabolism. New neuroprotective agents may target the factors that convey selective vulnerability.
Genetics and Environment. Each of the major neurodegenerative disorders may be familial in nature. HD is exclusively familial; it is transmitted by autosomal dominant inheritance, and the molecular mechanism of the genetic defect has been defined. Nevertheless, environmental factors importantly influence the age of onset and rate of progression of HD symptoms. PD, AD, and ALS are mostly sporadic without clear pattern of inheritance. But for each there are well-recognized genetic forms. For example, there are both dominant (α-synuclein, LRRK2) and recessive (parkin, DJ-1, PINK1) gene mutations that may give rise to PD (Farrer, 2006). In AD, mutations in the genes coding for the amyloid precursor protein (APP) and proteins known as the presenilins (involved in APP processing) lead to inherited forms of the disease (Selkoe and Podlisny, 2002). Mutations in the gene coding for copper-zinc super-oxide dismutase (SOD1) account for about 2% of the cases of adult-onset ALS (Boillée et al., 2006). Several other less common mutations have also been described.
In addition to these monogenic forms of neurodegenerative disease, there are also genetic risk factors that influence the probability of disease onset and modify the phenotype. For example, the apolipoprotein E (apo E) genotype constitutes an important risk factor for AD. Three distinct isoforms of this protein exist. Although all isoforms carry out their primary role in lipid metabolism equally well, individuals who are homozygous for the apoE4 allele ("4/4") have a much higher lifetime risk of AD than do those homozygous for the apoE2 allele ("2/2"). The mechanism by which the apoE4 protein increases the risk of AD is not exactly known. ApoE4 probably has multiple effects, some of which are mediated through altering β-amyloid (Aβ) aggregation or processing, and some of which that are Aβ-independent (Mahley et al., 2006).
Environmental factors including infectious agents, environmental toxins, and acquired brain injury have been proposed in the etiology of neurodegenerative disorders. The role of infection is best documented in the cases of PD that developed following the epidemic of encephalitis lethargica (Von Economo's encephalitis) in the early part of the 20th century. Most contemporary cases of PD are not preceded by encephalitis, and there is no convincing evidence for an infectious contribution to HD, AD, or ALS. Traumatic brain injury has been suggested as a trigger for neurodegenerative disorders, and in the case of AD there is some evidence to support this view (Cummings et al., 1998). At least one toxin, N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), can induce a condition closely resembling PD (Langston et al., 1983). More recently, evidence has linked pesticide exposure with PD (Costello et al., 2009). Exposure of soldiers to neurotoxic chemicals has been implicated in ALS (as part of "Gulf War syndrome") (Golomb, 2008). While these examples illustrate the potential of environmental factors to influence neurodegenerative disease, it is clear that the causes identified so far are too few to account for more than a small minority of the cases. Further progress in understanding the causes of neurodegenerative disorders will require a deeper understanding of the interactions between genetic predisposition and environmental factors, an area that is just beginning to be explored.
Common Cellular Mechanisms of Neurodegeneration. Despite their varied phenotypes, the neurodegenerative disorders share some common features. For example, misfolded and aggregated proteins are found in every major neurodegenerative disorder: alpha-synuclein, in PD; amyloid-β (Aβ) and tau in AD; huntingtin in HD; and SOD and TDP-43 in ALS. The accumulation of misfolded proteins may result from either genetic mutations producing abnormal structure, or from impaired cellular clearance. Age-related decline in the ability to clear misfolded proteins may be an important predisposing factor, and strategies to augment the clearance of misfolded proteins are being studied as potential therapies.
The term excitotoxicity describes the neural injury that results from the presence of excess glutamate in the brain. Glutamate is used as a neurotransmitter by many different neural systems and is believed to mediate most excitatory synaptic transmission in the mammalian brain (see Table 14–3). Although glutamate is required for normal brain function, the presence of excessive amounts of glutamate can lead to excitotoxic cell death (see Figure 14–13). The destructive effects of glutamate are mediated by glutamate receptors, particularly those of the N-methyl-D-aspartate (NMDA) type. Excitotoxic injury contributes to the neuronal death that occurs in acute processes such as stroke and head trauma (Choi and Rothman, 1990). The role of excitotoxicity is less certain in the chronic neurodegenerative disorders; nevertheless, regional and cellular differences in susceptibility to excitotoxic injury, conveyed, e.g., by differences in types of glutamate receptors, may contribute to selective vulnerability. This has led to the development of glutamate antagonists as neuroprotective therapies, with two such agents (memantine and riluzole, described later) currently in clinical use.
Aging is associated with a progressive impairment in the capacity of neurons for oxidative metabolism, perhaps in part because of a progressive accumulation of mutations in the mitochondrial genome. A consequence of impaired oxidative capacities is the production of reactive compounds such as hydrogen peroxide and oxygen radicals. Unchecked, these reactive species can lead to DNA damage, peroxidation of membrane lipids, and neuronal death. This has led to pursuit of drugs that can enhance cellular metabolism (such as the mitochondrial cofactor coenzyme Q10) and anti-oxidant strategies as treatments to prevent or retard degenerative diseases (Beal, 2005).
Clinical Overview. Parkinsonism is a clinical syndrome consisting of four cardinal features:
bradykinesia (slowness and poverty of movement)
resting tremor (which usually abates during voluntary movement)
an impairment of postural balance leading to disturbances of gait and falling
The most common form of parkinsonism is idiopathic PD, first described by James Parkinson in 1817 as paralysis agitans, or the "shaking palsy." The pathological hallmark of PD is the loss of the pigmented, dopaminergic neurons of the substantia nigra pars compacta, with the appearance of intracellular inclusions known as Lewy bodies. Progressive loss of dopamine (DA) containing neurons is a feature of normal aging; however, most people do not lose the 70-80% of dopaminergic neurons required to cause symptomatic PD. Without treatment, PD progresses over 5-10 years to a rigid, akinetic state in which patients are incapable of caring for themselves. Death frequently results from complications of immobility, including aspiration pneumonia or pulmonary embolism. The availability of effective pharmacological treatment has radically altered the prognosis of PD; in most cases, good functional mobility can be maintained for many years. Life expectancy of adequately treated patients is increased substantially, but overall mortality remains higher than that of the general population. In addition, while DA neuron loss is the most prominent feature of the disease, the disorder affects a wide range of other brain structures, including the brainstem, hippocampus, and cerebral cortex (Braak and Del Tredici, 2008). This pathology is likely responsible for the "non-motor" features of PD, which include sleep disorders, depression, and memory impairment. As treatments for the motor features have improved, these non-motor aspects have become important sources of disability for patients (Langston, 2006).
It is important to recognize that several disorders other than idiopathic PD also may produce parkinsonism, including some relatively rare neurodegenerative disorders, stroke, and intoxication with DA-receptor antagonists. Drugs that may cause parkinsonism include antipsychotics such as haloperidol and thorazine (Chapter 16) and anti-emetics such as prochloperazine and metoclopramide (Chapter 46). Although a complete discussion of the clinical diagnosis of parkinsonism exceeds the scope of this chapter, the distinction between idiopathic PD and other causes of parkinsonism is important because parkinsonism arising from other causes usually is refractory to all forms of treatment.
Pathophysiology. The dopaminergic deficit in PD arises from a loss of the neurons in the substantia nigra pars compacta that provide innervation to the striatum (caudate and putamen). The current understanding of the pathophysiology of PD is based on the finding that the striatal DA content is reduced in excess of 80%. This paralleled the loss of neurons from the substantia nigra, suggesting that replacement of DA could restore function (Cotzias et al., 1969; Hornykiewicz, 1973). These fundamental observations led to an extensive investigative effort to understand the metabolism and actions of DA and to learn how a deficit in DA gives rise to the clinical features of PD. We now have a model of the function of the basal ganglia that, while incomplete, is still useful.
Dopamine Synthesis, Metabolism, and Receptors. DA, a catecholamine, is synthesized in the terminals of dopaminergic neurons from tyrosine and stored, released, and metabolized by processes described in Chapter 13 and summarized in Figure 22–1. The actions of DA in the brain are mediated by a family of DA-receptor proteins. Two types of DA receptors were identified in the mammalian brain using pharmacological techniques: D1 receptors, which stimulate the synthesis of the intracellular second messenger cyclic AMP; and D2 receptors, which inhibit cyclic AMP synthesis as well as suppress Ca2+ currents and activate receptor-operated K+ currents. More recently, genetic studies revealed at least five distinct DA receptors (D1-D5) (Chapter 13). All the DA receptors are G protein–coupled receptors (GPCRs) (Chapter 3). The D1 and D5 proteins have a long intracellular carboxy-terminal tail and are members of the class defined pharmacologically as D1; they stimulate the formation of cyclic AMP and phosphatidyl inositol hydrolysis. The D2, D3, and D4 receptors share a large third intracellular loop and are of the D2 class. They decrease cyclic AMP formation and modulate K+ and Ca2+ currents. Each of the five DA receptor proteins has a distinct anatomical pattern of expression in the brain. The D1 and D2 proteins are abundant in the striatum and are the most important receptor sites with regard to the causes and treatment of PD. The D4 and D5 proteins are largely extrastriatal, whereas D3 expression is low in the caudate and putamen but more abundant in the nucleus accumbens and olfactory tubercle.
Neural Mechanism of Parkinsonism. Considerable effort has been devoted to understanding how the loss of dopaminergic input to the neurons of the neostriatum gives rise to the clinical features of PD (for review, see Albin et al., 1989; Mink and Thach, 1993; and Wichmann and DeLong, 1993). The basal ganglia can be viewed as a modulatory side loop that regulates the flow of information from the cerebral cortex to the motor neurons of the spinal cord (Figure 22–2). The neostriatum is the principal input structure of the basal ganglia and receives excitatory glutamatergic input from many areas of the cortex. Most neurons within the striatum are projection neurons that innervate other basal ganglia structures. A small but important subgroup of striatal neurons consists of interneurons that connect neurons within the striatum but do not project beyond its borders. Acetylcholine (ACh) and neuropeptides are used as transmitters by these striatal interneurons.
The outflow of the striatum proceeds along two distinct routes, termed the direct and indirect pathways. The direct pathway is formed by neurons in the striatum that project directly to the output stages of the basal ganglia, the substantia nigra pars reticulata (SNpr) and the globus pallidus interna (GPi); these, in turn, relay to the ventroanterior and ventrolateral thalamus, which provides excitatory input to the cortex. The neurotransmitter of both links of the direct pathway is γ-aminobutyric acid (GABA), which is inhibitory, so that the net effect of stimulation of the direct pathway at the level of the striatum is to increase the excitatory outflow from the thalamus to the cortex. The indirect pathway is composed of striatal neurons that project to the globus pallidus externa (GPe). This structure, in turn, innervates the subthalamic nucleus (STN), which provides outflow to the SNpr and GPi output stage. As in the direct pathway, the first two links—the projections from striatum to GPe and GPe to STN—use the inhibitory transmitter GABA; however, the final link—the projection from STN to SNpr and GPi—is an excitatory glutamatergic pathway. Thus, the net effect of stimulating the indirect pathway at the level of the striatum is to reduce the excitatory outflow from the thalamus to the cerebral cortex.
The key feature of this model of basal ganglia function, which accounts for the symptoms observed in PD as a result of loss of dopaminergic neurons, is the differential effect of DA on the direct and indirect pathways (Figure 22–3). The dopaminergic neurons of the substantia nigra pars compacta (SNpc) innervate all parts of the striatum; however, the target striatal neurons express distinct types of DA receptors. The striatal neurons giving rise to the direct pathway express primarily the excitatory D1 dopamine receptor protein, whereas the striatal neurons forming the indirect pathway express primarily the inhibitory D2 type. Thus, DA released in the striatum tends to increase the activity of the direct pathway and reduce the activity of the indirect pathway, whereas the depletion that occurs in PD has the opposite effect. The net effect of the reduced dopaminergic input in PD is to increase markedly the inhibitory outflow from the SNpr and GPi to the thalamus and reduce excitation of the motor cortex.
There are several limitations of this model of basal ganglia function (Parent and Cicchetti, 1998): The anatomical connections are considerably more complex than envisioned originally. In addition, many of the pathways involved use not just one, but several neurotransmitters. For example, the neuropeptides substance P and dynorphin are found predominantly in striatal neurons making up the direct pathway, whereas most of the indirect pathway neurons express enkephalin. These transmitters are expected to have slow modulatory effects on signaling, in contrast to the rapid effects of glutamate and GABA, but the functional significance of these modulatory effects remains unclear. Nevertheless, the model is useful and has important implications for the rational design and use of pharmacological agents in PD. First, it suggests that to restore the balance of the system through stimulation of DA receptors, the complementary effect of actions at both D1 and D2 receptors, as well as the possibility of adverse effects that may be mediated by D3, D4, or D5 receptors, must be considered. Second, it explains why replacement of DA is not the only approach to the treatment of PD. Drugs that inhibit cholinergic receptors have long been used for treatment of parkinsonism. Although their mechanisms of action are not completely understood, their effect is likely mediated at the level of the striatal projection neurons, which normally receive cholinergic input from striatal cholinergic interneurons. Only few clinically useful drugs for parkinsonism are presently available based on actions through GABA and glutamate receptors, even though both have crucial roles in the circuitry of the basal ganglia. However, they represent a promising avenue for drug development (Hallet and Standaert, 2004).
Dopaminergic nerve terminal. Dopamine (DA) is synthesized from tyrosine in the nerve terminal by the sequential actions of tyrosine hydrolase (TH) and aromatic amino acid decarboxylase (AADC). DA is sequestered by VMAT2 in storage granules and released by exocytosis. Synaptic DA activates presynaptic autoreceptors and postsynaptic D1 and D2 receptors. Synaptic DA may be taken up into the neuron via the DA and NE transporters (DAT, NET), or removed by postsynaptic uptake via OCT3 transporters. Cytosolic DA is subject to degradation by monoamine oxidase (MAO) and aldehyde dehydrogenase (ALDH) in the neuron, and by catechol-O-methyl tranferase (COMT) and MAO/ALDH in non-neuronal cells; the final metabolic product is homovanillic acid (HVA). See structures in Figure 22-4. PH, phenylalanine hydroxylase.
Schematic wiring diagram of the basal ganglia. The striatum is the principal input structure of the basal ganglia and receives excitatory glutamatergic input from many areas of cerebral cortex. The striatum contains projection neurons expressing predominantly D1 or D2 dopamine receptors, as well as interneurons that use ACh as a neurotransmitter. Outflow from the striatum proceeds along two routes. The direct pathway, from the striatum to the substantia nigra pars reticulata (SNpr) and globus pallidus interna (GPi), uses the inhibitory transmitter GABA. The indirect pathway, from the striatum through the globus pallidus externa (GPe) and the subthalamic nucleus (STN) to the SNpr and GPi, consists of two inhibitory GABAergic links and one excitatory glutamatergic projection (Glu). The substantia nigra pars compacta (SNpc) provides dopaminergic innervation to the striatal neurons, giving rise to both the direct and indirect pathways, and regulates the relative activity of these two paths. The SNpr and GPi are the output structures of the basal ganglia and provide feedback to the cerebral cortex through the ventroanterior and ventrolateral nuclei of the thalamus (VA/VL).
The basal ganglia in Parkinson disease. The primary defect is destruction of the dopaminergic neurons of the SNpc. The striatal neurons that form the direct pathway from the striatum to the SNpr and GPi express primarily the excitatory D1 DA receptor, whereas the striatal neurons that project to the GPe and form the indirect pathway express the inhibitory D2 dopamine receptor. Thus, loss of the dopaminergic input to the striatum has a differential effect on the two outflow pathways; the direct pathway to the SNpr and GPi is less active (structures in purple), whereas the activity in the indirect pathway is increased (structures in red). The net effect is that neurons in the SNpr and GPi become more active. This leads to increased inhibition of the VA/VL thalamus and reduced excitatory input to the cortex. Light blue lines indicate primary pathways with reduced activity. (See legend to Figure 22–2 for definitions of anatomical abbreviations.)
Treatment of Parkinson Disease
Commonly used medications for the treatment of PD are summarized in Table 22–1.
Table 22-1Commonly Used Medications for the Treatment of Parkinson Disease ||Download (.pdf) Table 22-1 Commonly Used Medications for the Treatment of Parkinson Disease
Levodopa. Levodopa (l-DOPA, larodopa, L-3,4-dihydroxyphenylalanine), the metabolic precursor of DA, is the single most effective agent in the treatment of PD. Levodopa is itself largely inert; both its therapeutic and adverse effects result from the decarboxylation of levo-dopa to DA. When administered orally, levodopa is absorbed rapidly from the small bowel by the transport system for aromatic amino acids. Concentrations of the drug in plasma usually peak between 0.5 and 2 hours after an oral dose. The t1/2 in plasma is short (1-3 hours). The rate and extent of absorption of levodopa depends on the rate of gastric emptying, the pH of gastric juice, and the length of time the drug is exposed to the degradative enzymes of the gastric and intestinal mucosa. Competition for absorption sites in the small bowel from dietary amino acids also may have a marked effect on the absorption of levodopa; administration of levodopa with high-protein meals delays absorption and reduces peak plasma concentrations. Entry of the drug into the CNS across the blood-brain barrier also is mediated by a membrane transporter for aromatic amino acids, and competition between dietary protein and levodopa may occur at this level. In the brain, levodopa is converted to DA by decarboxylation primarily within the presynaptic terminals of dopaminergic neurons in the stratium. The DA produced is responsible for the therapeutic effectiveness of the drug in PD; after release, it is either transported back into dopaminergic terminals by the presynaptic uptake mechanism or metabolized by the actions of MAO and catechol-O-methyltransferase (COMT) (Figure 22–4).
Metabolism of levodopa (l-DOPA). ALDH, aldehyde dehydrogenase; COMT, catechol-O-methyltransferase; DβH, dopamine β-hydroxylase; AADC, aromatic l-amino acid decarboxylase; MAO, monoamine oxidase.
In clinical practice, levodopa is almost always administered in combination with a peripherally acting inhibitor of aromatic l-amino acid decarboxylase, such as carbidopa or benserazide (available outside the U.S.), drugs that do not penetrate well into the CNS. If levodopa is administered alone, the drug is largely decarboxylated by enzymes in the intestinal mucosa and other peripheral sites so that relatively little unchanged drug reaches the cerebral circulation and probably <1% penetrates the CNS. In addition, DA release into the circulation by peripheral conversion of levodopa produces undesirable effects, particularly nausea. Inhibition of peripheral decarboxylase markedly increases the fraction of administered levodopa that remains unmetabolized and available to cross the blood-brain barrier (Figure 22–5) and reduces the incidence of GI side effects.
Pharmacological preservation of l-DOPA and striatal dopamine. The principal site of action of inhibitors of catechol-O-methyltransferase (COMT) (such as tolcapone and entacapone) is in the peripheral circulation. They block the O-methylation of levodopa (l-DOPA) and increase the fraction of the drug available for delivery to the brain. Tolcapone also has effects in the CNS. Inhibitors of MAO-B, such as low-dose selegiline and rasagiline, will act within the CNS to reduce oxidative deamination of DA, thereby enhancing vesicular stores. AADC, aromatic l-amino acid decarboxylase; DA, dopamine; DOPAC, 3,4-dihydroxyphenylacetic acid; MAO, monoamine oxidase; 3MT, 3-methoxyltyramine; 3-O-MD, 3-O-methyl DOPA
In most individuals, a daily dose of 75 mg carbidopa is sufficient to prevent the development of nausea. For this reason, the most commonly prescribed form of carbidopa/levodopa (sinemet, atamet, others) is the 25/100 form, containing 25 mg carbidopa and 100 mg levodopa. With this formulation, dosage schedules of three or more tablets daily provide acceptable inhibition of decarboxylase in most individuals. Occasionally, individuals will require larger doses of carbidopa to minimize gastrointestinal side effects, and administration of supplemental carbidopa (lodosyn) may be beneficial. Carbidopa/ levodopa is also available in an orally disintegrating tablet (parcopa). This may be useful in patients with swallowing difficulty, although it is important to note that levodopa is not absorbed through the oral mucosa, and must still be delivered to the small intestine for absorption. Thus, the time to onset of action of PARCOPA is not appreciably different from that of standard oral formulations.
Levodopa therapy can have a dramatic effect on all the signs and symptoms of PD. Early in the course of the disease, the degree of improvement in tremor, rigidity, and bradykinesia may be nearly complete. In early PD, the duration of the beneficial effects of levodopa may exceed the plasma lifetime of the drug, suggesting that the nigrostriatal DA system retains some capacity to store and release DA. A principal limitation of the long-term use of levodopa therapy is that with time this apparent "buffering" capacity is lost, and the patient's motor state may fluctuate dramatically with each dose of levodopa, a condition described as motor complications of levodopa. A common problem is the development of the "wearing off" phenomenon: each dose of levodopa effectively improves mobility for a period of time, perhaps 1-2 hours, but rigidity and akinesia return rapidly at the end of the dosing interval. Increasing the dose and frequency of administration can improve this situation, but this often is limited by the development of dyskinesias, excessive and abnormal involuntary movements. Dyskinesias are observed most often when the plasma levodopa concentration is high, although in some individuals dyskinesias or dystonia may be triggered when the level is rising or falling. These movements can be as uncomfortable and disabling as the rigidity and akinesia of PD. In the later stages of PD, patients may fluctuate rapidly between being "off," having no beneficial effects from their medications, and being "on" but with disabling dyskinesias, a situation called the on/off phenomenon.
Recent evidence has indicated that induction of motor complications may be the result of an active process of adaptation to variations in brain and plasma levodopa levels. This process of adaptation is apparently complex, involving not only alterations in the function of DA receptors but also downstream changes in the postsynaptic striatal neurons, including modification of NMDA glutamate receptors (Hallett and Standaert, 2004). When levodopa levels are maintained constant by intravenous infusion, dyskinesias and fluctuations are greatly reduced, and the clinical improvement is maintained for up to several days after returning to oral levodopa dosing (Mouradian et al., 1990). A sustained-release formulation consisting of carbidopa/levodopa in an erodable wax matrix (sinemet cr) has been marketed in an attempt to produce more stable plasma levodopa levels than can be obtained with oral administration of standard carbidopa/levodopa formulations. This formulation is helpful in some cases, but absorption of the sustained-release formulation is not entirely predictable. Other approaches to more continuous delivery of levodopa, including gel and transdermal formulations, are under study.
An important unanswered question regarding the use of levodopa in PD is whether this medication alters the course of the underlying disease or merely modifies the symptoms. A recent randomized trial has provided evidence that levodopa does not have an adverse effect on the course of the underlying disease, but has also confirmed that high doses of levodopa are associated with early onset of dyskinesias (Fahn et al., 2004). Most practitioners have adopted a pragmatic approach, using levodopa only when the symptoms of PD cause functional impairment and other treatments are inadequate or not well tolerated.
In addition to motor complications and nausea, several other adverse effects may be observed with levodopa treatment. A frequent and troubling adverse effect is the induction of hallucinations and confusion, especially in elderly patients or in patients with preexisting cognitive dysfunction. This adverse effect often limits the ability to treat parkinsonian symptoms adequately. Conventional antipsychotic agents, such as the phenothiazines, are effective against levodopa-induced psychosis but may cause marked worsening of parkinsonism, probably through actions at the D2 DA receptor. An alternative approach has been to use "atypical" antipsychotic agents (Chapter 16). However, not all of these are equally useful in this setting, and some of the "atypical" agents may nevertheless worsen PD symptoms. The two drugs which appear to be most effective and best tolerated in patients with advanced PD are clozapine and quetiapine (Friedman and Factor, 2000).
Peripheral decarboxylation of levodopa and release of DA into the circulation may activate vascular DA receptors and produce orthostatic hypotension. Administration of levodopa with nonspecific inhibitors of MAO, such as phenelzine and tranylcypromine, markedly accentuates the actions of levodopa and may precipitate life-threatening hypertensive crisis and hyperpyrexia; nonspecific MAO inhibitors always should be discontinued at least 14 days before levodopa is administered (note that this prohibition does not include the MAO-B subtype-specific inhibitors selegiline and rasagiline (azilect), which, as discussed later, are often administered safely in combination with levodopa). Abrupt withdrawal of levodopa or other dopaminergic medications may precipitate the neuroleptic malignant syndrome of confusion, rigidity, and hyperthermia, a potentially lethal adverse effect.
Dopamine-Receptor Agonists. An alternative to levodopa is the use of drugs that are direct agonists of striatal DA receptors, an approach that offers several potential advantages. Since enzymatic conversion of these drugs is not required for activity, they do not depend on the functional capacities of the nigrostriatal neurons. The DA receptor agonists in clinical use have durations of action substantially longer than that of levodopa; they are often used in the management of dose-related fluctuations in motor state, and may be helpful in preventing motor complications. Finally, it has been suggested that DA receptor agonists may have the potential to modify the course of PD by reducing endogenous release of DA as well as the need for exogenous levodopa, thereby reducing free radical formation.
Two orally administered DA receptor agonists are commonly used for treatment of PD: ropinirole (requip) and pramipexole (mirapex).
These agents are better tolerated and have largely replaced the older agents (e.g., bromocriptine, pergolide), which have to be titrated more slowly. Pergolide was withdrawn from the U.S. market in 2007 because of cardiac valve fibrosis. Ropinirole and pramipexole have selective activity at D2 class sites (specifically at the D2 and D3 receptor) and little or no activity at D1 class sites. Both are well absorbed orally and have similar therapeutic actions. Like levodopa, they can relieve the clinical symptoms of PD. The duration of action of the DA agonists (8-24 hours) often is longer than that of levodopa (6-8 hours), and they are particularly effective in the treatment of patients who have developed on/off phenomena. Ropinirole is also available in a once-daily sustained release formulation (requip xl), which is more convenient and may reduce adverse effects related to intermittent dosing. Both pramipexole and ropinirole may produce hallucinosis or confusion, similar to that observed with levodopa, and may cause nausea and orthostatic hypotension. They should be initiated at low dose and titrated slowly to minimize these effects. The DA agonists, as well as levodopa itself, are also associated with fatigue and somnolence. The somnolence in some cases may be quite severe, and several instances of sudden attacks of irresistible sleepiness leading to motor vehicle accidents have been reported (Frucht et al., 1999). Although an uncommon complication, it is prudent to advise patients of this possibility and to switch to another agent when somnolence is an issue.
Apomorphine. Apomorphine (apokyn) is a dopaminergic agonist that can be administered by subcutaneous injection. It has high affinity for D4 receptors; moderate affinity for D2, D3, D5, and adrenergic α1D, α2B, and α2C receptors; and low affinity for D1 receptors. Apomorphine has been used in Europe for many years and is FDA-approved as a "rescue therapy" for the acute intermittent treatment of "off" episodes in patients with a fluctuating response to dopaminergic therapy.
Apomorphine has the same side effects as discussed earlier for the oral DA agonists. In addition, apomorphine is highly emetogenic and requires pre- and post-treatment anti-emetic therapy. Oral trimethobenzamide (tigan), at a dose of 300 mg three times daily, should be started 3 days prior to the initial dose of apomorphine and continued at least during the first 2 months of therapy. Profound hypotension and loss of consciousness have occurred when apomorphine was administered with ondansetron; hence, the concomitant use of apomorphine with antiemetic drugs of the 5-HT3 antagonist class is contraindicated. Other potentially serious side effects of apomorphine include QT prolongation, injection-site reactions, and the development of a pattern of abuse characterized by increasingly frequent dosing leading to hallucinations, dyskinesia, and abnormal behavior. Because of these potential adverse effects, use of apomorphine is appropriate only when other measures, such as oral DA agonists or COMT inhibitors, have failed to control the "off" episodes. Apomorphine therapy should be initiated with a 2-mg test dose in a setting where the patient can be monitored carefully. If tolerated, it can be titrated slowly up to a maximum dosage of 6 mg. For effective control of symptoms, patients may require three or more injections daily.
Catechol-O-Methyltransferase (COMT) Inhibitors. Drugs for the treatment of PD include inhibitors of the enzyme COMT, which, together with MAO, metabolizes levodopa and DA. COMT transfers a methyl group from the donor S-adenosyl-L-methionine, producing the pharmacologically inactive compounds 3-O-methyl DOPA (from levodopa) and 3-methoxytyramine (from DA; Figure 22–5). When levodopa is administered orally, nearly 99% of the drug is metabolized and does not reach the brain. Most is converted by aromatic l-amino acid decarboxylase (AADC) to DA, which causes nausea and hypotension. Addition of an AADC inhibitor such as carbidopa reduces the formation of DA but increases the fraction of levodopa that is methylated by COMT. The principal therapeutic action of the COMT inhibitors is to block this peripheral conversion of levodopa to 3-O-methyl DOPA, increasing both the plasma t1/2 of levodopa as well as the fraction of each dose that reaches the CNS.
Two COMT inhibitors presently are available for this use in the United States, tolcapone (tasmar) and entacapone (comtan). In double-blind clinical trials, both agents significantly reduced the "wearing off" symptoms in patients treated with levodopa/carbidopa (Parkinson Study Group, 1997). The two drugs differ only in their pharmacokinetic properties and adverse effects: tolcapone has a relatively long duration of action, allowing for administration two to three times a day, and appears to act by both central and peripheral inhibition of COMT. Entacapone has a short duration of action (2 hours) and usually is administered simultaneously with each dose of levodopa/carbidopa. The action of entacapone is attributable principally to peripheral inhibition of COMT. The common adverse effects of these agents are similar to those of levodopa/carbidopa alone and include nausea, orthostatic hypotension, vivid dreams, confusion, and hallucinations. An important adverse effect associated with tolcapone is hepatotoxicity. Up to 2% of the patients treated have increased serum alanine aminotransferase and aspartate transaminase; and at least three fatal cases of fulminant hepatic failure in patients taking tolcapone have been observed, leading to addition of a black box warning to the label. At present, tolcapone should be used only in patients who have not responded to other therapies and with appropriate monitoring for hepatic injury. Entacapone has not been associated with hepatotoxicity and requires no special monitoring. Entacapone also is available in fixed-dose combinations with levodopa/carbidopa (stalevo).
Selective MAO-B Inhibitors. Two isoenzymes of MAO oxidize monoamines. While both isoenzymes (MAO-A and MAO-B) are present in the periphery and inactivate monoamines of intestinal origin, the isoenzyme MAO-B is the predominant form in the striatum and is responsible for most of the oxidative metabolism of DA in the brain. Two selective MAO-B inhibitors are used for the treatment of PD: selegiline (eldepryl, emsam, zelapar) and rasagiline (azilect). When used at recommended doses, these agents selectively inactivate MAO-B through irreversible inhibition of the enzyme (Elmer and Bertoni, 2008). Both agents exert modest beneficial effects on the symptoms of PD. The basis of this efficacy is presumed to be the inhibition of breakdown of DA in the striatum. Unlike nonspecific inhibitors of MAO (such as phenelzine, tranylcypromine, and isocarboxazid), selective MAO-B inhibitors do not substantially inhibit the peripheral metabolism of catecholamines and can be taken safely with levodopa. These agents also do not exhibit the "cheese effect," the potentially lethal potentiation of catecholamine action observed when patients on nonspecific MAO inhibitors ingest indirectly acting sympathomimetic amines such as the tyramine found in certain cheeses and wine.
Selegiline has been used for many years as a symptomatic treatment for PD and is generally well tolerated in younger patients with early or mild PD. In patients with more advanced PD or underlying cognitive impairment, selegiline may accentuate the adverse motor and cognitive effects of levodopa therapy. Metabolites of selegiline include amphetamine and methamphetamine, which may cause anxiety, insomnia, and other adverse symptoms. Recently, selegiline has become available in an orally disintegrating tablet (zelepar) as well as a transdermal patch (emsam). Both of these delivery routes are intended to reduce hepatic first-pass metabolism and limit the formation of the amphetamine metabolites.
Unlike selegiline, rasagiline does not give rise to undesirable amphetamine metabolites. In randomized controlled clinical trials, rasagiline monotherapy was effective in early PD. Adjunctive therapy significantly reduced levodopa-related "wearing off" symptoms in advanced PD.
A consequence of the inhibition of MAO-B in the brain is a reduction in the overall catabolism of DA, which may reduce the formation of potentially toxic free radicals. This observation has led to studies which have examined the question of whether MAO-B inhibition can alter the rate of neurodegeneration in PD. The potential protective role of selegiline in idiopathic PD was evaluated in several multicenter randomized trials; although there was some evidence supporting a neuroprotective effect, the outcomes were obscured by the difficulty of distinguishing long-term neuroprotective effects from short-term symptomatic effects (Parkinson Study Group, 1993; Yacoubian and Standaert, 2008). A more recent study, using a different design, has produced more convincing data suggesting a neuroprotective effect of rasagiline (Olanow, 2008).
Although selective MAO-B inhibitors are generally well tolerated, drug interactions can be troublesome. Similar to the nonspecific MAO inhibitors, selegiline can lead to the development of stupor, rigidity, agitation, and hyperthermia when administered with the analgesic meperidine. Although the mechanics, of this interaction is uncertain, selegiline or rasagiline should not be given in combination with meperidine. Adverse effects have been reported from co-administration of MAO-B inhibitors with tricyclic antidepressants or with serotonin-reuptake inhibitors. However, interactions with antidepressants are uncommon, and many patients do take these combinations of medications without apparent adverse interaction; nonetheless, concomitant administration of selegiline or rasagiline with serotonergic drugs should be done with caution, especially in patients on high doses of serotonin-reuptake inhibitors.
Muscarinic Receptor Antagonists. Antagonists of muscarinic acetylcholine receptors were used widely for the treatment of PD before the discovery of levodopa. The biological basis for the therapeutic actions of anticholinergics is not completely understood. They may act within the neostriatum through the receptors that normally mediate the response to intrinsic cholinergic innervation of this structure, which arises primarily from cholinergic striatal interneurons. Several muscarinic cholinergic receptors have been cloned (Chapters 9 and 14); like the DA receptors, these are GPCRs. Five subtypes of muscarinic receptors exist. All five subtypes are probably present in the striatum, although each one has a distinct distribution (Hersch et al., 1994). Anticholinergic drugs currently used in the treatment of PD include trihexyphenidyl (2-4 mg three times per day), benztropine mesylate (1-4 mg two times per day), and diphenhydramine hydrochloride (25-50 mg three or four times per day). Diphenhydramine also is a histamine H1 antagonist (Chapter 32).
All of these drugs have relatively modest antiparkinsonian activity and are only used in the treatment of early PD or as an adjunct to dopamimetic therapy. Adverse effects result from their anticholinergic properties. Most troublesome are sedation and mental confusion. Other side effects are constipation, urinary retention, and blurred vision through cycloplegia. All anticholinergic drugs must be used with caution in patients with narrow-angle glaucoma (Chapter 65).
Amantadine. Amantadine (symmetrel), an antiviral agent used for the prophylaxis and treatment of influenza A (Chapter 58), has antiparkinsonian activity. Amantadine appears to alter DA release in the striatum, has anticholinergic properties, and blocks NMDA glutamate receptors. However, it is not well understood which of amantadine's pharmacological effects are responsible for its antiparkinsonian actions. In any case, the effects of amantadine in PD are modest. It is used as initial therapy of mild PD. It also may be helpful as an adjunct in patients on levodopa with dose-related fluctuations and dyskinesias. The antidyskinetic properties of amantadine have been attributed to actions at NMDA receptors (Hallett and Standaert, 2004), although the closely related NMDA receptor antagonist memantine (discussed later) does not seem to have this effect.
Amantadine is usually administered at a dose of 100 mg twice a day and is well tolerated. Dizziness, lethargy, anticholinergic effects, and sleep disturbance, as well as nausea and vomiting, have been observed occasionally, but even when present, these effects are mild and reversible.
Neuroprotective Treatments for Parkinson Disease. It would be desirable to identify a treatment that modifies the progressive degeneration that underlies PD rather than simply controlling the symptoms. Current research strategies are based on the disease mechanisms described earlier (e.g., energy metabolism, oxidative stress, environmental triggers, and excitotoxicity) and on discoveries related to the genetics of PD (Yacoubian and Standaert, 2008). Several studies have examined the potential neuroprotective effects of existing medications. In a randomized controlled trial, levodopa did not worsen the disease state. Some benefits persisted for several weeks after treatment was stopped, but whether this was truly a "neuroprotective" effect remains uncertain (Fahn et al., 2004).
Two trials have attempted to examine the effect of pramipexole or ropinirole on neurodegeneration in PD (Parkinson Study Group, 2002; Whone et al., 2003). Both trials observed that in patients treated with either one of these agonists, there was a reduced rate of loss of markers of dopaminergic neurotransmission measured by brain imaging compared with a similar group of patients treated with levodopa. These intriguing data should be viewed cautiously, particularly because there is considerable uncertainty about the relationship of the imaging results techniques used and the true rate of neurodegeneration (Albin and Frey, 2003).
Inhibition of MAO-B in the brain reduces the overall catabolism of DA, which may decrease the formation of potentially toxic free radicals and consequently the rate of neurodegeneration in PD. The protective role of selegiline in idiopathic PD was evaluated in several multicenter randomized trials. Unfortunately, distinguishing long-term neuroprotective effects from short-term symptomatic effects was difficult in the earlier studies (Parkinson Study Group, 1993; Yacoubian and Standaert, 2008). A different study design showed more convincingly a neuroprotective effect of rasagiline (2008).
Another strategy under study is the use of compounds that augment cellular energy metabolism such coenzyme Q10, a cofactor required for the mitochondrial electron-transport chain. A small study has demonstrated that this drug is well tolerated in PD and has suggested that coenzyme Q10 may slow the course of the disease (Shults et al., 2002). A much larger study is in progress. Therapies directly targeting the molecules which are implicated in the pathogenesis of PD are still in a nascent stage, and may require unconventional delivery strategies such as gene therapy (Lewis and Standaert, 2008).
Clinical Summary. Pharmacological treatment of PD should be tailored to the individual patient. Drug therapy is not obligatory in early PD; many patients can be managed for a time with exercise and lifestyle interventions. For patients with mild symptoms, MAO-B inhibitors, amantadine, or (in younger patients) anticholinergics are reasonable choices. In most patients, treatment with a dopaminergic drug, either levodopa or a DA agonist, is eventually required. Large controlled clinical trials provide convincing evidence for a reduced rate of motor fluctuation in patients in which DA agonists are used as initial treatment. This benefit was, however, accompanied by an increased rate of adverse effects, especially somnolence and hallucinations (Parkinson Study Group, 2000; Rascol et al., 2000). Practitioners prefer DA agonist as initial therapy in younger patients in order to reduce the occurrence of motor complications. In older patients or those with substantial comorbidity, levodopa/ carbidopa is generally better tolerated.